The adult central nervous system (CNS) has a very limited intrinsic ability to regenerate after injury. Traumatic brain injuries or neurodegenerative diseases cause neuronal cell leads to long-lasting functional impairments. The profound effect observed from these injuries results from a series of events that occurs immediately following injury and persists for several weeks. These events take place not only at the intrinsic level via intracellular signaling pathways but at the extrinsic level as well. Recent evidence indicates that in order to promote significant regeneration in the damaged CNS, a combinatorial approach addressing both the intrinsic and extrinsic barriers to regeneration is necessary. Our goal is to understand how modification of the post-injury microenvironment will affect nerve regeneration. Specifically, our hypothesis is that transplantation of neural progenitor cells (NPCs) into the retina combined with administration of an epidermal growth factor receptor (EGFR) inhibitor via an engineered construct will enhance nerve regeneration in an optic nerve axotomy model. This hypothesis is based on two observations: (1) NPCs can differentiate into neurons and incorporate into existing neural networks, and (2) administration of EGFR inhibitors to damaged optic nerve and spinal cord result in regeneration of injured neurons. We will use an optic nerve crush injury model to determine the effectiveness of our treatment. At the site of injury, we will implant a polymer construct allowing controlled delivery of the EGFR inhibitor, followed by injection of NPCs into the vitreous of the eye. Our specific aims are to: (1) develop and characterize a drug delivery system for the controlled release of the EGFR inhibitor, (2) develop and characterize a construct for in vivo delivery of the inhibitor at the injury site, and (3) assess the effects of a combinatorial treatment approach on nerve regeneration in vivo in an optic nerve injury model. Combinatorial treatments provide a promising new option for therapy in CNS repair. We believe this approach in conjunction with cell transplantation therapy will provide important information regarding nerve regeneration in the mature >CNS. Accomplishing the specific aims outlined will provide an understanding of nerve regeneration and the glial scar microenvironment in vivo. Relevance: The central nervous system has very limited repair capabilities. This limitation is due to neuronal cell death and a post-injury cellular environment that is not favorable to regrowth of nerves. A combinatorial treatment of transplantation of neural progenitor cells and administration of an epidermal growth factor inhibitor can address both of these factors simultaneously, thus providing a new avenue for therapy.